Mechanisms of Homeostasis and Invasive Cell Migration in Skin Tumorigenesis

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The long term goal of this proposal is to understand how growth promoting and restricting signals interact to balance one another and how their deregulation leads to the development of neoplastic tumors which often turn into malignant, metastatic carcinomas. My preliminary data revealed that loss of TGF-(3 receptor 11 (TpRll) function in the skin epithelium produces spontaneous anal and genital squamous cell carcinomas (SCCs) and cooperates with active H-Ras to form metastatic SCCs. Focal adhesion kinase (FAK) mediated integrin signaling is hyperactive in these carcinomas and cultured keratinocytes suggesting a direct link between TpRIl loss and FAK activation. Indeed, FAK has been reported to be the most commonly hyperactivated non receptor tyrosine kinase in epithelial tumors and tumor cell lines, yet its functions and molecular targets are largely unknown. The central hypothesis tested by this proposal is that FAK plays a central role in the development of SCCs in T(3Rii deficient skin epithelium. This hypothesis will be tested experimentally by: 1) assessing the probabilities to develop spontaneous anal and genital, or chemically induced SCCs in skin of WT, TpRll and FAK single and TpRll/FAK double conditional mutant mice and investigating the underlying cellular and pathological alterations; 2) identification of molecular mechanisms by which loss of TpRll function in keratinocytes promotes FAK activation; and 3) investigate how loss of TpRll and increased FAK activity promote skin carcinogenesis, malignant progression, and invasive metastatic keratinocyte migration. Data generated from the proposed experiments will advance our understanding of the molecular functions of TpRlliand FAK mediated integrin signaling in normal development and disease, identify the molecular mechanisms by which growth promoting Ras and Integrin signaling interact with growth restrictihg TGF-p signaling to control not only proliferation, but also ceil survival, cytoskeletal dynamics and invasive cell migration, and identify novel molecular pathways by which carcinomas form even in the absence of FAK fiintion. Together, this proposal will strengthen our molecular and cellular understanding of carcinoQehesis and will reveal potential therapeutic targets. .